Association of Daratumumab Use With Ocular Events in a Case Series of US Adults

Abstract

This case series uses postmarketing data to evaluate the association of daratumumab use with ocular events such as acute angle-closure glaucoma, myopic shift, and choroidal effusions among US adults.

Daratumumab is a CD38-directed monoclonal antibody that was initially approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of multiple myeloma. During routine surveillance, we identified postmarketing cases of acute angle-closure glaucoma (AACG), myopic shift, and choroidal effusions with daratumumab use from the FDA Adverse Event Reporting System (FAERS) and the literature. We reviewed postmarketing data to investigate a potential association between daratumumab use and these ocular events.

Methods

Under statutory authority pursuant to public health, no approval from institutional review boards or informed consent was required for this case series analysis. We reviewed the FAERS, PubMed, and Embase databases through September 20, 2020, to identify cases of AACG, myopic shift, and choroidal effusions with daratumumab. Reports were excluded if there was insufficient information to confirm the temporal drug-event sequence, if an alternative etiology was considered the likely cause of the event, or if report details were insufficient for assessment.

Results

Our case series comprised 17 patients with 23 postmarketing ocular events, including 11 patients (64.7%) identified in the FAERS database and 6 from the literature (35.3%; Table). The median age was 45 years (range, 33-76 years); there were 12 women (70.6%) and 5 men (29.4%). Of the 23 reported events included in this analysis, 13 (56.5%) were myopic shift, 7 were choroidal effusions (30.4%), and 3 were AACG (13.0%). The most common presenting symptom was reduced visual acuity (reported by 15 patients [88.2%]); this reduced visual acuity occurred bilaterally for the 11 patients who reported this information. The median time to onset of the ocular event was 1 day (range, 1-1 day) from the start of daratumumab use. Nine patients (52.9%) reported an unremarkable ocular history, 4 (23.5%) reported a history of cataracts, 1 (5.9%) reported a history of serous chorioretinopathy, and 3 (17.6%) did not report an ocular history. Three patients (17.6%) reported using the combination of sulfamethoxazole and trimethoprim concomitantly; no other confounding medications were reported.

Table. Descriptive Characteristics of Patients With Ocular Events Associated With Daratumumab Use^a.

Characteristic	Value
Case source (n = 17)
FAERS	11 (64.7)
Literature	6 (35.3)
Type of event (n = 23)b
Myopic shift	13 (56.5)
Choroidal effusion	7 (30.4)
Acute angle-closure glaucoma	3 (13.0)
Age (n = 16)c
Mean (SD), y	53 (15.9)
Median (range), y	45 (33-76)
Sex (n = 17)
Women	12 (70.6)
Men	5 (29.4)
Country (n = 17)
US	8 (47.1)
Other	9 (52.9)
Reported indication for daratumumab use (n = 17)
Amyloidosis	1 (5.9)
Multiple myeloma	14 (82.4)
Other	1 (5.9)
Not reported	1 (5.9)
Time to onset of ocular event, median (range), d	1 (1-1)

Abbreviation: FAERS, Food and Drug Administration Adverse Event Reporting System.

^a Data are presented as the number (percentage) of patients unless specified otherwise. Owing to rounding, percentages may not total 100%.

^b More than 1 event may have been reported per case.

^c Age was not reported for 1 patient.

Discussion

Acute angle-closure glaucoma is an ophthalmic emergency that requires immediate medical intervention to prevent permanent ocular injury. Medications represent an important cause of AACG, which typically occurs through nonpupillary or pupillary block mechanisms, with the latter occurring more commonly among patients with an anatomic predisposition to a closed angle.¹ Nonpupillary block drug-induced AACG is considered an idiosyncratic reaction that is often attributable to the development of choroidal effusions.^1,2

This case series mirrors the spectrum of clinical findings described with nonpupillary block drug-induced causes of AACG (eg, topiramate), which often consists of acute myopia and/or narrowing of the anterior chamber angle as a result of choroidal effusions.^1,2 Moreover, the timing of the ocular events relative to daratumumab use in the present case series is consistent with other medications associated with nonpupillary block AACG and suggests daratumumab as the likely cause.^1,3 Although use of sulfamethoxazole plus trimethoprim has been associated with AACG, none of the patients in the present series receiving this combination described ocular symptoms before starting daratumumab. In addition, the baseline ocular disorders reported in some cases (eg, cataracts) are not expected risk factors for nonpupillary block AACG; therefore, they were not considered relevant confounding factors in this analysis.

Although the exact mechanism for these ocular events is not fully understood, it is likely related to the anti-CD38 properties of daratumumab. The nonpigmented epithelium of the ciliary body, where choroidal effusions may develop, expresses CD38.⁴ Therefore, the inhibitory effects of daratumumab on CD38 expression represent a possible mechanism by which daratumumab may cause this toxic reaction.

Our analysis is limited by the quality of spontaneous adverse event reporting and other limitations inherent to spontaneous reporting systems (eg, underreporting, reporting biases). The US prescribing information for daratumumab was updated in 2022 to include acute myopia, choroidal effusions, and AACG, with recommendations for patients to discontinue daratumumab when ocular toxicity is suspected and to seek immediate ophthalmologic evaluation.^5,6 The revised prescribing information will help increase clinicians’ awareness of these risks and mitigate serious outcomes by improving early identification and appropriate intervention.